AAV-mediated gene therapy demonstrates phenotypic rescue in a mouse model of Cockayne syndrome

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Abstract

Cockayne syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span, and a progressive degeneration of the central nervous system. Loss-of-function mutations in CSA result in deficiencies in transcription-coupled nucleotide excision repair. Currently, no therapies are available for these patients. Adeno-associated virus–mediated (AAV-mediated) gene therapy offers an opportunity to address this unmet need. We designed an AAV vector encoding human CSA under a ubiquitous promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal intracerebroventricular injection in the Csa–/– Xpa–/– mouse model. Treatment with AAV9-CSA resulted in a significant increase in life span, and broad distribution of human CSA in the brain and heart, without evidence of vector-related toxicity. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, and neuropathologic alterations, including hypomyelination, astrocytosis, and microgliosis, as well as likely life-limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for clinical translation of an AAV gene therapy for patients with CS into humans.

Authors

Ana Rita Batista, Aine C. Scholand, William S. Callahan, McKenna K. Watson, Cassandra M. Sion, Tyler Mola, Kennedy O’Hara, Simon A. Wentworth, William S. Sena-Esteves, Oliver D. King, Robert M. King, Miguel Sena-Esteves